Abstract Opioid addiction has reached epidemic levels and imposes a tremendous socioeconomic burden in the United States. Repetitive drug use forms powerful memories associating drug-evoked experiences with its proximal environmental cues. These memories are major obstacles for successfully treating addiction, since even after a prolonged period of abstinence, re-exposure to such cues often triggers craving that promotes relapse. Sleep is important for memory consolidation and opioid addicts have a disrupted sleep/wake cycle. Whether the sleep disorder in opioid addicts contributes to the long-lasting opioid-associated memories is largely unknown. In our preliminary studies, we found that a polysynaptic pathway from the paraventricular nucleus of the thalamus (PVT) to the lateral hypothalamus (LH) plays an important role in the maintenance of the opioid-associated memories. Disruption of neural activities in either the PVT-to-NAcc or the NAcc-to-LH pathway can block the retrieval of the opioid-associated memories and prevent relapse. Interestingly, hypocretin (Hcrt) neurons in the LH strongly innervate the PVT and this is required for maintaining the wakefulness. Given the well-established roles of the Hcrt neurons in drug seeking, we hypothesis that the PVT-NAcc-LH (Hcrt)-PVT loop links sleep disorders in opioid addicts with their long-lasting drug- associated memories. In this proposal, we propose to (1) determine whether Hcrt neurons in the LH are the major target of the NAcc input; (2) examine whether manipulating the LH (Hcrt)-PVT pathway can effectively prevent relapse; and (3) test whether sleep intervention could be an effective strategy to prevent relapse. Our work will inspire the development of novel strategy to treat opioid abuse.